Adamantyl containing 1,4-oxazinone derivatives

ABSTRACT

Antimicrobial or anti-inflammatory 1,4-oxazinone derivatives of the structure: ##STR1## wherein one of R and R 1  is hydrogen and the other is --CH 2  CO 2  R 6  (R 6  =alkyl) or R and R 1  together represent the group ═CHCO 2  R 6 , R 2  and R 3  are hydrogen, alkyl, substituted alkyl, phenyl or substituted phenyl or R 2  and R 3  together represent a single adamantyl group, and R 4  and R 5  are hydrogen, alkyl, substituted alkyl, phenyl, substituted phenyl, or benzyl, are disclosed herein.

FIELD OF THE INVENTION

This invention relates to new 1,4-oxazinone derivatives. Moreparticularly, it relates to derivatives of3,4,5,6-tetrahydro-1,4-oxazin-2-one. These derivatives, when tested,were found to have antimicrobial activity against N. gonorrehoeae oranti-inflammatory activity against carrageenan-induced edema in alaboratory animal model.

STATEMENT OF THE INVENTION

Accordingly, this invention is a 1,4-oxazinone derivative of the formula##STR2## wherein one of R and R¹ is hydrogen and the other representsthe group --CH₂ CO₂ R⁶ or together R and R¹ represent the group ═CHCO₂R⁶ where R⁶ is alkyl, one of R² and R³ is hydrogen and the other isalkyl, substituted alkyl, phenyl or substituted phenyl or R² and R³together represent a single adamantyl group, and R⁴ and R⁵ are hydrogen,alkyl, substituted alkyl, phenyl or substituted phenyl, or benzyl.

DETAILED DESCRIPTION OF INVENTION

The compounds of this invention are 3,4,5,6-tetrahydro-1,4-oxazin-2-onederivatives wherein the substituent groups, as shown in the abovestructural formula, are designated R through R⁵.

It is preferred that R and R¹ represent the group ═CHCO₂ R⁶ is a loweralkyl radical (C₁ -C₈) but one of R and R¹ may also be hydrogen whilethe other must then be --CH₂ CO₂ R⁶. R⁶ may have up to 30 carbons, butpreferably less than four carbons.

The alkyl radicals of R² and R³ have up to thirty carbon atoms,preferably up to eight and more preferably less than four carbon atoms.The alkyl portion of the substituted alkyl radicals of R² and R³ alsohas up to 30 carbon atoms, but preferably less than four. Thesubstituents of these alkyl radicals are, for example, hydroxy, andalkanoyloxy groups. Alternatively, R² and R³ together represent a singleadamantyl group. In particular, R² and R³ represent the adamantylsubstituent of a compound of the following formula: ##STR3##

The aromatic radicals which are represented by R²⁻⁵ are, for example,phenyl and benzyl.

R⁴ and R⁵ are preferably hydrogen, alkyl radicals having less than fourcarbon atoms that may be substituted with a hydroxyl group, or a benzylgroup.

The above mentioned alkyl radicals for R through R⁶ are either straightor branched chained. Examples of these include methyl, ethyl, propyl,isopropyl, isobutyl, butyl, pentyl, isopentyl, hexyl, octyl, isooctyl,decyl, dodecyl, octadecyl, eicosanoyl, tricosanoyl, hexacosanoyl,triacontanoyl and the like. In general, the 1,4-oxazinones of thisinvention may be prepared by reacting a dialkyl (C₁ -C₈)acetylenedicarboxylate with a compound having both amino and hydroxysubstituent groups which will condense with the acetylene compound toform the corresponding 1,4-oxazinone derivative. The aminoalcoholreactant is preferably dissolved in a suitable inert organic solvent,for example, a lower alkanol, ether, alkyl acetate, alkane or mixturesof these. The reaction is usually carried out with reactants employed inequimolar amounts, at ambient temperature and atmospheric pressure butmay be run at temperatures ranging from about 15° to 80° C.

EXAMPLES

The following examples are used to show the preparation ofrepresentative compounds of this invention.

EXAMPLE 1

3-(Methoxycarbonyl)methylene-spiro[3,4,5,6-tetrahydro-1,4-oxazin-2-one-6,2'-tricyclo[3.3.1.1³,7]decane] was prepared as follows: 2-aminomethyl-2-hydroxyadamantane(2.70 g, 0.015 mol) was dissolved in 40 ml of anhydrous ethanol. Afterstirring for several minutes at room temperature, the solution wastreated dropwise with 1.84 ml (0.015 mol) of dimethylacetylenedicarboxylate. The reaction mixture was stirred at roomtemperature for 21/4 hours, then the solvent was removed in vacuo toleave 3.3 g (77%) of the desired 1,4-oxazinone derivative. Mp 227°-229°C. (ethanol).

Anal. Calcd. for C₁₆ H₂₁ NO₄ : C, 65.96; H, 7.26; N, 4.81. Found: C,65.80; H, 7.44; N, 4.85.

The above prepared derivative was reduced as follows to form3-(methoxycarbonyl)methyl-spiro[3,4,5,6-tetrahydro-1,4-oxazin-2-one-6,2'-tricyclo[3.3.1.1³,7]decane]. The derivative (13.0 g) was dissolved in acetic acid andhydrogenated in a Parr apparatus over 2.62 g platinum oxide. Thehydrogenation was run at room temperature for 21/2 hours at pressurethat did not exceed 1 atm. After workup and recrystallization frommethanol, 8.80 g of the pure 3-(methoxycarbonyl)methyl analog wasobtained. Mp 103°-107° C.

Anal. Calcd. for C₁₆ H₂₃ NO₄ : C, 65.51; H, 7.90; N, 4.77. Found: C,64.55; H, 7.53; N, 4.72.

EXAMPLE 2

5,5-Dimethyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazine-2-onewas prepared as follows: 2-amino-2-methyl-1-propanol (5.35 ml, 0.056mol) was dissolved in 100 ml of anhydrous ethanol. Dimethylacetylenedicarboxylate (7.20 ml, 0.056 mol) was added dropwise at a ratewhich caused the solution to mildly reflux. Then, the reaction mixturewas stirred at ambient temperature for 2 hours, and the solvent wasevaporated to yield the desired 1,4-oxazinone derivative. Afterrecrystallization from ethanol, 5.79 g of pure product was obtainedmelting at 94°-97° C.

Anal. Calcd. for C₉ H₁₃ NO₄ : C, 54.26; H, 6.58; N, 7.03. Found: C,54.42; H, 6.39; N, 6.96.

EXAMPLES 3-12

The following analogs of the 1,4-oxazinone derivative of Example 2 wereprepared in a manner similar to the procedure used in Example 2. Byreacting dimethyl acetylenedicarboxylate with 2-hydroxypropylamine,2-amino-1-ethanol, 3-amino-2-hydroxy-1-propanol, 2-amino-1-phenyl-1-propanol, 2-amino-1-phenyl-1-ethanol,2-amino-2-hydroxymethyl-1-propanol, 2-amino-3-phenyl-1-propanol,2-amino-1-butanol, and 2-amino-3-methyl-1-butanol, in place of2-amino-2-methyl-1-propanol of Example 2 the following compounds ofExamples 3-12 were prepared:

EXAMPLE 3

6-methyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one.The recrystallization solvent was ethanol and the melting point was98°-101° C.

Anal. Calcd. for C₈ H₁₁ NO₄ : C, 51.89; H, 5.99; N, 7.56. Found: C,51.86; H, 5.99; N, 7.56.

EXAMPLE 4

3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one. Therecrystallization solvent was ethanol and the melting point was 76°-79°C.

Anal. Calcd. for C₇ H₉ NO₄ : C, 49.12; H, 5.30; N, 8.18. Found: C,48.76; H, 5.32; N, 8.04.

EXAMPLE 5

6-hydroxymethyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2one.The recrystallization solvent was ethanol and the melting point was112°-114° C.

Anal. Calcd. for C₈ H₁₁ NO₅ : C, 47.76; H, 5.51; N, 6.96. Found: C,47.93; H, 5.55; N, 6.95.

EXAMPLE 6

5-methyl-6-phenyl-(3-methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one.The recrystallization solvent was diethyl ether and the melting pointwas 117° C.

Anal. Calcd. for C₁₄ H₁₅ NO₄ : C, 64.36; H, 5.79; N, 5.36. Found: C,64.29; H, 5.82; N, 5.40.

EXAMPLE 7

6-phenyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one.The recrystallization solvent was ethanol and the melting point was125°-126° C.

Anal. Calcd. for C₁₃ H₁₃ NO₄ : C, 63.15; H, 5.30; N, 5.66. Found: C,63.02; H, 5.44; N, 5.61.

EXAMPLE 8

5-hydroxymethyl-5-methyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one.The recrystallization solvent was hexane and the melting point was62°-63° C.

Anal. Calcd. for C₉ H₁₃ NO₅ : C, 50.23; H, 6.09; N, 6.51. Found: C,50.60; H, 6.30; N, 6.52.

EXAMPLE 9

5-benzyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one.The recrystallization solvent was hexane and the melting point was82°-83° C.

Anal. Calcd. for C₁₄ H₁₅ NO₄ : C, 64.36; H, 5.79; N, 5.36. Found: C,64.56; H, 5.93; N, 5.35.

EXAMPLE 10

5-ethyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazine-2-one.The recrystallization solvent was hexane-ethylacetate (1:1) and themelting point was 68°-70° C.

Anal. Calcd. C₉ H₁₃ NO₄ : C, 54.26; H, 6.59; N, 7.03. Found: C, 54.11;H, 6.37; N, 7.04.

EXAMPLE 11

5-isopropyl-3-(methoxycarbonyl)methylene-3,4,5,6-tetrahydro-1,4-oxazin-2-one.This material was a viscous oil.

We claim:
 1. A 1,4-oxazinone derivative of the formula ##STR4## whereinone of R and R¹ is hydrogen and the other represents the group --CH₂ CO₂R⁶ or together R and R¹ represent the group ═CHCO₂ R⁶ where R⁶ is alkyl,R² and R³ together represent a single adamantyl group, and R⁴ and R⁵ arehydrogen, alkyl, substituted alkyl, phenyl, substituted phenyl, orbenzyl.
 2. The derivative of claim 1 wherein R and R¹ together representthe group ═CHCO₂ R⁶ where R⁶ is a lower alkyl radical.
 3. The derivativeof claim 2 wherein R² and R³ together represent a single adamantyl groupand R⁴ and R⁵ are hydrogen.
 4. The derivative of claim 1 wherein one ofR and R¹ is hydrogen and the other is --CH₂ CO₂ R⁶ where R⁶ is a loweralkyl radical.
 5. The derivative of claim 4 wherein R² and R³ togetherrepresent a single adamantyl group, and R⁴ and R⁵ are hydrogen.
 6. Thederivative of claim 4 wherein R² and R³ are hydrogen, and R⁴ and R⁵ arealkyl radicals having less than 4 carbon atoms.